# Effects of Hepatic Acetyl-CoA Carboxylase Inhibition on NAFLD and Hepatic Insulin Resistance

> **NIH NIH R01** · YALE UNIVERSITY · 2021 · $729,407

## Abstract

Non alcoholic fatty liver disease (NAFLD) is estimated to affect up to one third of the general population and
there is a strong relationship between NAFLD, hepatic insulin resistance and type 2 diabetes (T2D). NAFLD is
also a key predisposing factor for the development of non-alcoholic steatohepatitis (NASH), cirrhosis and
hepatocellular carcinoma and it is anticipated that NAFLD-induced NASH will soon surpass hepatitis C and
alcoholic cirrhosis as the most common indication for liver transplantation in the USA. Therefore there is a
great unmet need for new drugs that are effective at reducing hepatic steatosis and hepatic insulin resistance.
In this grant we will examine the chronic effects of a novel liver-targeted small molecule inhibitor of acetyl-CoA
carboxylase on hepatic triglyceride content as well as hepatic glucose and lipid metabolism in NAFLD subjects
in a randomized double-blinded placebo-controlled parallel group study. Specifically we will examine the
chronic (21 days) effects of a novel liver-targeted small molecule inhibitor of acetyl-CoA carboxylase on: 1)
Hepatic triglyceride content assessed by 1H magnetic resonance spectroscopy (MRS), 2) Hepatic, skeletal
muscle and adipocyte insulin sensitivity assessed by a hyperinsulinemic-euglycemic clamp in conjunction with
[6,6-2H2]glucose, [2H5]glycerol, and [13C16]palmitate turnover, 3) Rates of hepatic mitochondrial oxidation
directly assessed by in vivo 13C magnetic resonance spectroscopy, 4) Rates of hepatic ketogenesis assessed
by [13C4]β-hydroxybutyrate turnover, 5) Hepatic de novo lipogenesis (DNL) and gluconeogenesis assessed by
2H2O, 6) Relative flux rates of hepatic pyruvate carboxylase flux (VPC)/citrate synthase flux (VCS) assessed by a
novel Positional Isotopomer NMR Tracer Analysis (PINTA) method and 7) Whole body energy expenditure,
VO2, VCO2, respiratory quotient assessed by indirect calorimetry. We hypothesize that chronic inhibition of
acetyl-CoA carboxylase will result in decreased hepatic steatosis due to increased hepatic mitochondrial fat
oxidation and decreased DNL. We also anticipate that this reduction in hepatic steatosis will be associated with
improved hepatic insulin sensitivity as reflected by increased suppression of hepatic glucose production during
a hyperinsulinemic-euglycemic clamp. The results of these studies will provide important new proof of concept
data in support of liver-targeted acetyl CoA carboxylase inhibition as a therapy for NAFLD and T2D as well as
fundamental new insights into the mechanisms by which liver-targeted acetyl CoA carboxylase inhibition
reduces hepatic steatosis, decreases hepatic insulin resistance and alters hepatic mitochondrial fat oxidation.
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## Key facts

- **NIH application ID:** 10217114
- **Project number:** 5R01DK113984-05
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** GERALD I SHULMAN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $729,407
- **Award type:** 5
- **Project period:** 2017-09-15 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10217114

## Citation

> US National Institutes of Health, RePORTER application 10217114, Effects of Hepatic Acetyl-CoA Carboxylase Inhibition on NAFLD and Hepatic Insulin Resistance (5R01DK113984-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10217114. Licensed CC0.

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